Novel Imaging Finding and Novel Mutation in an Infant with Molybdenum Cofactor Deficiency, a Mimicker of Hypoxic-Ischaemic Encephalopathy

Molybdenum cofactor deficiency is a rare metabolic disorder manifesting with early onset seizures, developmental delay, microcephaly, and spasticity. In this report, we describe a three-month-old infant with neonatal onset, poorly controlled seizures, developmental delay, microcephaly, spastic quadriparesis and visual insufficiency. Magnetic resonance imaging of brain had shown cystic encephalomalacia involving bilateral parieto-occipital lobe and elevated lactate in magnetic resonance spectroscopy. Restricted diffusion noted along the corticospinal tract in our case is a novel imaging finding in patients with molybdenum cofactor deficiency. Low serum uric acid and elevated urine sulfite excretion were observed. A novel homozygous mutation was detected in exon 4 of molybdenum cofactor synthesis 2 (MOCS2) gene. Early infantile or neonatal onset seizures, developmental delay, microcephaly and cystic encephalomalacia in neuroimaging mimicking hypoxic-ischaemic encephalopathy should raise the suspect for molybdenum cofactor deficiency. Screening of all neonates for urinary sulfite metabolites would help in early diagnosis and management. Early diagnosis and treatment with cyclic pyranopterin monophosphate could arrest the progression of molybdenum cofactor deficiency type A. More research is needed to explore further treatment options in this otherwise lethal disorder.


Introduction
Molybdenum cofactor deficiency (MOCD) is a rare metabolic disorder with neurological symptoms of neonatal onset, developmental delay, seizures and motor abnormalities, first described in 1978 (1). If undiagnosed, this disorder can result in rapid progressive encephalopathy and death. Early diagnosis is important in this lethal disorder as treatment with cyclic pyranopterin monophosphate (cPMP) could arrest the progression of MOCD type A (2).
We describe an infant with MOCD having early onset refractory seizures and imaging findings mimicked hypoxic-ischemic encephalopathy.
Restricted diffusion was noted along the corticospinal tract in our patient.
It is a novel imaging finding in patients with MOCD and a novel mutation Abstract Molybdenum cofactor deficiency is a rare metabolic disorder manifesting with early onset seizures, developmental delay, microcephaly, and spasticity.In this report, we describe a three-month-old infant with poorly controlled seizures of neonatal onset, developmental delay, microcephaly, spastic quadriparesis and cortical visual impairment. Magnetic resonance imaging of brain had shown cystic encephalomalacia involving bilateral parieto-occipital lobe and elevated lactate in magnetic resonance spectroscopy. Restricted diffusion noted along the corticospinal tract in our case is a novel imaging finding in patients with molybdenum cofactor deficiency. Low serum uric acid and elevated urine sulfite excretion were observed. A novel homozygous mutation was detected in exon 4 of molybdenum cofactor synthesis 2 (MOCS2) gene. Early infantile or neonatal onset seizures, developmental delay, microcephaly and cystic encephalomalacia in neuroimaging mimicking hypoxic-ischaemic encephalopathy should raise the suspect for molybdenum cofactor deficiency. Screening of all neonates for urinary sulfite metabolites would help in early diagnosis and management. Early diagnosis and treatment with cyclic pyranopterin monophosphate could arrest the progression of molybdenum cofactor deficiency type A. More research is needed to explore further treatment options in this otherwise lethal disorder. Keywords: Seizure; Encephalomalacia; Sulfite; Molybdenum cofactor was also detected in the exon 4 of molybdenum cofactor synthesis 2 (MOCS2) gene.

Case report
A three-month-old boy born first in birth order to a non-consanguineously married Indian couple was referred for the evaluation of global developmental delay and refractory seizures. Informed consent was taken from the mother. Mother had no antenatal risk factors. The baby was delivered full term by normal vaginal delivery with a birth weight of 3200 g. Neonatal transition was uneventful.
Jaundice was noticed on third day of life and the maximum bilirubin recorded was 16.3 mg/dL.

Fig 2: MRI brain T1 sagittal image (A) shows diffuse thinning of corpus callosum (white arrow); brainstem appear normal and cerebellum also appear normal (double arrows). DWI (B) and ADC (C) images show restricted diffusion along corticospinal tracts at the corona radiata (white arrows).
clinical, radiological findings and biochemical markers. MOCS1 and MOCS2 genes were sequenced by Sanger sequencing (primer sequences and conditions are available on request). with MOCD deficiency (8,9). Elevated lactate peak was observed in our patient as described in a previous report (2). It could possibly be due to energy failure resulting from neurotoxic effect of sulfite on the mitochondria.  (11)(12)(13)(14).
In conclusion, MOCD must be considered in all neonates and infants with microcephaly, refractory seizures, and developmental delay with or without ectopia lentis. Infants with MOCD have distinctive imaging findings mimicking hypoxic-ischaemic encephalopathy. Screening of all neonates for urinary sulfite metabolites helps in early diagnosis.
More research is needed to explore further treatment options in this otherwise lethal disorder.

Acknowledgement
We acknowledge Sathish Kumar Loganathan who helped in the clinical care of the patient.

Author's contribution
Sangeetha Yoganathan provided clinical care to the patient and prepared the initial manuscript.
Sniya Valsa Sudhakar revised the manuscript and prepared the images.
Atanu Kumar Dutta and Sumita Danda established the genetic diagnosis and revised the manuscript.
Mahalakshmi Chandran helped in the laboratory diagnosis and revised the manuscript.
Maya Thomas supervised the patient care and critically reviewed the manuscript. All the authors have approved the final manuscript.